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For chemical structures of these agents, see Table 18-1 in the 11th edition of the parent text.

*Antipsychotic agents for use in children under age 12 years include chlorpromazine, chlorprothixene (>6 years), thioridazine, and triflupromazine (among agents of low potency); and prochlorperazine and trifluoperazine (>6 years) (among agents of high potency). Haloperidol (orally) has also been used extensively in children.

^Except for the enanthate and decanoate forms of fluphenazine and haloperidol decanoate, dosage can be given intramuscularly up to every 6 hours for agitated patients. Haloperidol lactate has been given intravenously; this is experimental.

Adverse Cardiovascular and Cerebrovascular Effects The most common adverse cardiovascular effect is orthostatic hypotension, which may result in syncope, falls, and injuries. Hypotension is most likely to occur with administration of the phenothiazines with aliphatic side chains or atypical antipsychotics. Potent neuroleptics generally produce less hypotension.

Some antipsychotic agents depress cardiac repolarization, as reflected in the QT interval corrected for heart rate (QTc). Prolongations above 500 msec can be dangerous clinically, particularly by increasing the risk of torsades de pointes, which often is a precursor of fatal cardiac arrest (see Chapter 34). Such cardiac depressant effects are especially prominent with thioridazine and its active metabolite, mesoridazine, as well as pimozide, high doses of haloperidol, and ziprasidone. These drugs are used cautiously, if at all, in combination with other agents with known cardiac-depressant effects, including tricyclic antidepressants (see Chapter 17), certain antiarrhythmic agents (see Chapter 34), other antipsychotics with similar actions (such as pimozide and thiori-dazine), or specific DA antagonists (cisapride and metoclopramide; see Chapter 37). Clozapine has rarely been associated with myocarditis and cardiomyopathy. Some clinical observations have suggested increased risk of stroke among elderly patients treated with risperidone and perhaps olanza-pine. The clinical significance of these uncommon cardiac and cerebrovascular events remains uncertain.

Adverse Neurological Effects Many neurological syndromes, particularly involving the extrapyramidal motor system, occur following the use of most antipsychotic drugs, especially with the high-potency D2-receptor antagonists (tricyclic piperazines and butyrophenones). Acute adverse extrapyramidal effects are less likely with aripiprazole, clozapine, quetiapine, thioridazine, and ziprasidone, or low doses of olanzapine or risperidone.

Six distinct neurological syndromes are characteristic of older neuroleptic-antipsychotic drugs. Four of these (acute dystonia, akathisia, parkinsonism, and the rare neuroleptic malignant syndrome) usually appear soon after administration of the drug. Two (tardive dyskinesias or dysto-nias, and rare perioral tremor) are late-appearing syndromes that evolve during prolonged treatment. The clinical features of these syndromes and guidelines for their management are summarized in Table 18-1.

Certain therapeutic guidelines should be followed to minimize the neurological syndromes that complicate the use of antipsychotic drugs. Routine use of antiparkinson agents in an attempt to avoid early extrapyramidal reactions adds complexity, side effects, and expense to the regimen. Antiparkinson agents are best reserved for cases of overt extrapyramidal reactions that respond favorably to such intervention. The need for such agents for the treatment of acute dystonic reactions ordinarily diminishes with time, but parkinsonism and akathisia typically persist. The thoughtful and conservative use of antipsychotic drugs, particularly modern atypical agents, in patients with chronic or frequently recurrent psychotic disorders almost certainly can reduce the risk of tardive dyskinesia. Although reduction of the dose of an antipsychotic agent is the best way to minimize its adverse neurological effects, this may not be practical in a patient with uncontrollable psychotic illness. The best preventive practice is to use the minimum effective dose of an antipsy-chotic drug. The growing number of modern atypical antipsychotic agents with a low risk of inducing extrapyramidal side effects provides an alternative for many patients.

Weight Gain and Metabolic Effects Weight gain and its associated long-term complications can occur with extended treatment with most antipsychotic and antimanic drugs. Weight gain is especially prominent with clozapine and olanzapine; somewhat less with quetiapine; even less with fluphenazine, haloperidol, and risperidone; and very low with aripiprazole, molindone, and ziprasi-done. Adverse effects of weight gain likely include increased risk of new-onset or worsening of type 2 diabetes mellitus, hypertension, and hyperlipidemia. In some patients with morbid increases in weight, the airway may be compromised (Pickwickian syndrome), especially during sleep (including sleep apnea).

Blood Dyscrasias Mild leukocytosis, leukopenia, and eosinophilia occasionally occur with antipsychotic treatment, particularly with clozapine and less often with phenothiazines of low potency. It is difficult to determine whether leukopenia that develops during the administration of such agents is a forewarning of impending agranulocytosis. This serious complication occurs in not more than 1 in 10,000 patients receiving chlorpromazine or other low-potency agents (other than clozapine); it usually appears within the first 8-12 weeks of treatment.

Bone marrow suppression, or less commonly agranulocytosis, has been associated with the use of clozapine. The incidence approaches 1% within several months of treatment, independent of dose, without regular monitoring of white blood cell counts. Because blood dyscrasia may develop suddenly, the appearance of fever, malaise, or apparent respiratory infection in a patient being treated with an antipsychotic drug should be followed immediately by a complete blood count. Risk of agranulocytosis is greatly reduced, though not eliminated, by frequent white blood cell counts in patients being treated with clozapine, as is required in the U.S. (weekly for 6 months and biweekly thereafter). The safety of resuming even low doses of clozapine or other antipsychotics following recovery from agranulocytosis should not be assumed.

Skin Reactions

Dermatological reactions to the phenothiazines, including urticaria or dermatitis, occur in ~5% of patients receiving chlorpromazine. Contact dermatitis may occur in personnel who handle chlorpromazine, and there may be a degree of cross-sensitivity to other phenothiazines. Sunburn and photosensitivity resembling severe sunburn occur and require use of an effective sunscreen preparation. Epithelial keratopathy often is observed in patients on long-term therapy with chlor-promazine, and opacities in the cornea and in the lens of the eye have been noted. Pigmentary retinopathy has been reported, particularly following doses of thioridazine in excess of1000 mg/day. A maximum daily dose of800 mg currently is recommended. Dermatological reactions to modern atypical antipsychotic agents are uncommon.

GI and Hepatic Effects

A mild jaundice, typically occurring early in therapy, may be seen in some patients receiving chlorpromazine. Pruritus is rare. The reaction probably is a manifestation of hypersensitivity, because eosinophilia and eosinophilic infiltration of the liver occur. For uninterrupted drug therapy in a patient with neuroleptic-induced jaundice, it probably is safest to use low doses of a potent, dissimilar agent. Hepatic dysfunction with other antipsychotic agents is uncommon. Clozapine can cause potentially severe ileus and sialorrhea.

INTERACTIONS WITH OTHER DRUGS The phenothiazines and thioxanthenes, especially those of lower potency, affect the actions of a number of other drugs. Antipsychotic drugs can strongly potentiate the effect of medically prescribed sedatives and analgesics, alcohol, nonpre-scription sedatives and hypnotics, antihistamines, and cold remedies. Chlorpromazine increases the miotic and sedative effects of morphine and may increase its analgesic actions. The drug markedly increases the respiratory depression produced by meperidine and can be expected to have similar effects when administered concurrently with other opioids. Obviously, neuroleptic drugs inhibit the actions of dopaminergic agonists and levodopa and worsen the neurological symptoms of Parkinson's disease.

The antimuscarinic action of clozapine and thioridazine can cause tachycardia and enhance the peripheral and central effects (confusion, delirium) of other anticholinergic agents, such as the tricyclic antidepressants and antiparkinson agents.

Sedatives or anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and pheny-toin, but not valproate) that induce CYPs (see Chapter 3) can enhance the metabolism of antipsy-chotic and many other agents (including anticoagulants and oral contraceptives), sometimes with significant clinical consequences. Conversely, selective serotonin (5-HT) reuptake inhibitors including fluvoxamine, fluoxetine, paroxetine, venlafaxine, sertraline, and nefazodone (see Chapter 17) compete for these enzymes and can elevate circulating levels of neuroleptics.

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